bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–04–13
34 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. To EMT or not to EMT: Ablation of mesenchymal tumor cell lineages reveals the essential role of EMT in pancreatic cancer initiation and evolution.
  2. Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
  3. Lipid Exchange Assay in Living Cells.
  4. Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia.
  5. Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
  6. Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.
  7. Lipidome atlas of p53 mutant variants in pancreatic cancer.
  8. Ductal or Ngn3+ cells do not contribute to adult pancreatic islet beta-cell neogenesis in homeostasis.
  9. No Evidence for Plasma Membrane Potential-Independent Cell Penetrating Peptide Direct Translocation.
  10. Recommendations for robust and reproducible research on ferroptosis.
  11. Phase separation of the PRPP amidotransferase into dynamic condensates promotes de novo purine synthesis in yeast.
  12. PLK1 blockade enhances the anti-tumor effect of MAPK inhibition in pancreatic ductal adenocarcinoma.
  13. Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
  14. Mechanisms of ferroptosis sensitization and resistance.
  15. Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.
  16. Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties.
  17. KRASG12D cells override homeostatic cell elimination mechanisms in adult pancreas via Wnt5a and cell dormancy.
  18. A neuroimmune circuit mediates cancer cachexia-associated apathy.
  19. Interferon-induced PARP14-mediated ADP-ribosylation in p62 bodies requires the ubiquitin-proteasome system.
  20. Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
  21. Estrogenic activity of E2-conjugated GLP-1 is mediated by intracellular endolysosomal acidification and estrone metabolism.
  22. Mechanistic insights from simulations of drug-drug conjugate nanoclusters for co-delivery across cancer cell membranes.
  23. Nuclear envelope-associated lipid droplets are enriched in cholesteryl esters and increase during inflammatory signaling.
  24. The autophagy protein ATG-9 regulates lysosome function and integrity.
  25. Contact-free characterization of nuclear mechanics using correlative Brillouin-Raman Micro-Spectroscopy in living cells.
  26. Stress dynamically modulates neuronal autophagy to gate depression onset.
  27. A Novel Platform for Precise Senolysis.
  28. Integrating cancer medicine into metabolic rhythms.
  29. Espin enhances confined cell migration by promoting filopodia formation and contributes to cancer metastasis.
  30. Cell Confluency Affects p53 Dynamics in Response to DNA Damage.
  31. Peripheral positioning of lysosomes supports melanoma aggressiveness.
  32. Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis.
  33. The role of the hypothalamus in the development of cancer cachexia.
  34. From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.
  1. Cancer Res. 2025 Apr 08.
    To EMT or not to EMT: Ablation of mesenchymal tumor cell lineages reveals the essential role of EMT in pancreatic cancer initiation and evolution.
    Jessica Peura, Calvin Johnson, Jason R Pitarresi.
      Epithelial-to-mesenchymal transition (EMT), a complex biological pathway that facilitates cellular plasticity, is used by tumor cells to enable metastasis and drug resistance. Our functional understanding of the impact of EMT on cancer has been limited by the lack of effective tools to ablate tumor cells as they become mesenchymal. In a recent study published in Nature, Perelli and colleagues used elegant genetically engineered lineage tracing and ablation strategies to track and eliminate tumor cells as they undergo EMT in pancreatic cancer. In a two-pronged approach, they queried the functional consequences of ablating EMT tumor cells before pancreatic ductal adenocarcinoma (PDAC) formation or in advanced PDAC tumors. These experiments collectively revealed that epithelial tumor cells only progress to low-grade lesions with minimal proliferative potential, while mesenchymal tumor cells undergo EMT early on to become malignant and metastasize. Profiling of mesenchymal tumor cell lineages revealed an altered chromatin landscape that leads to chromosomal instability (CIN) and disease progression. CIN is facilitated through complex structural rearrangements and chromothripsis, ultimately driving increased tumor heterogeneity and enhanced proliferation in EMT cells. This work reveals that EMT is an important driver of tumor heterogeneity and progression as a downstream consequence of CIN and provides mechanistic insight into how cellular plasticity can lead to genomic changes that drive disease progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1443
  2. J Clin Invest. 2025 Apr 08. pii: e178806. [Epub ahead of print]
    Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
    Andrew C D'Lugos, Jeremy B Ducharme, Chandler S Callaway, Jose G Trevino, Carl Atkinson, Sarah M Judge, Andrew R Judge.
      Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross-sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild type (WT) mice, or mice with genetic deletion of the central complement component 3 (C3-/- mice). Compared to WT mice, C3-/- mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation is contributory to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.
    Keywords:  Cancer; Muscle; Muscle biology; Oncology; Proteomics
    DOI:  https://doi.org/10.1172/JCI178806
  3. J Vis Exp. 2025 Mar 21.
    Lipid Exchange Assay in Living Cells.
    Sanjna Rana, Antonio Torlentino, Pavana Suresh, W Todd Miller, Erwin London.
      Lipid rafts are dynamic, ordered domains in the plasma membrane often formed during membrane protein clustering and signaling. The lipid identity of the outer leaflet drives the membrane's propensity to form lipid rafts. The transient nature of lipid rafts makes it difficult to study in living cells. Therefore, methods that add or remove raft-forming lipids at the outer leaflet of living cells facilitate studying the characteristics of rafts, such as their effects on membrane proteins. Lipid exchange experiments developed in our lab utilize lipid-loaded cyclodextrins to remove and add exogenous phospholipids to change the lipid constitution of the plasma membrane. Substituting the membrane with a raft or non-raft-forming lipid can aid in studying the effects on transmembrane protein activity. Here, we describe a method for lipid exchange on the outer leaflet of the plasma membrane using lipid-loaded cyclodextrin. We demonstrate the preparation of the exchange media and the subsequent treatment of attached mammalian cells. We also showcase how to measure the efficiency of exchange using HP-TLC. This protocol yields a nearly complete replacement of the outer leaflet with exogenous lipids without altering cellular viability, permitting further experimentation on modified intact plasma membranes.
    DOI:  https://doi.org/10.3791/68008
  4. Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2417290122
    Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia.
    Frank Charbonier, Junqin Zhu, Raleigh Slyman, Cole Allan, Ovijit Chaudhuri.
      Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large-scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell-substrate interactions at the tissue scale.
    Keywords:  cell–substrate interactions; collective cell migration; mechanotransduction; tissue mechanics; viscoelastic substrates
    DOI:  https://doi.org/10.1073/pnas.2417290122
  5. J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]
    Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
    Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.
      Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.
    Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation
    DOI:  https://doi.org/10.1242/jcs.263688
  6. Cell. 2025 Apr 04. pii: S0092-8674(25)00282-X. [Epub ahead of print]
    Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.
    Andrew Murley, Ann Catherine Popovici, Xiwen Sophie Hu, Anina Lund, Kevin Wickham, Jenni Durieux, Larry Joe, Etai Koronyo, Hanlin Zhang, Naomi R Genuth, Andrew Dillin.
      To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.
    Keywords:  aging; endoplasmic reticulum; lysosome; mTOR; macroautophagy; protein aggregates; quiescence
    DOI:  https://doi.org/10.1016/j.cell.2025.03.009
  7. Biol Direct. 2025 Apr 11. 20(1): 51
    Lipidome atlas of p53 mutant variants in pancreatic cancer.
    Kian Cotton, Charley Comer, Sabrina Caporali, Alessio Butera, Stephanie Gurres, Francesco Capradossi, Angelo D'Alessandro, Ivano Amelio, Maria Victoria Niklison-Chirou.
      Mutations in the tumour suppressor protein p53 are present in 70% of human pancreatic ductal adenocarcinomas (PDAC), subsequently to highly common activation mutation of the oncogene KRAS. These p53 mutations generate stable expression of mutant proteins, such as p53R175H and p53R273H, which do not retain p53 wild type function. In this study, we investigated the impact of two specific p53 mutant variants on lipid metabolism of pancreatic cancer. Lipids critically participate to tumorigenesis with to their roles in membrane biosynthesis, energy storage and production of signalling molecules. Using cell lines derived from mouse models of PDAC generated by knock-in p53 alleles carrying point mutations at codons R172H and R270H (equivalent to R175H and R273H in humans), we found that silencing p53R172H and p53R270H in pancreatic cancer cells significantly alters lipid metabolism, with patterns of common and variant specific changes. Specifically, loss of p53R172H in these cells reduces lipid storage. Additionally, silencing either p53R172H or p53R270H individually leads to marked increases in lysophospholipid levels. These findings offer new insights into the lipidome reprogramming induced by the loss of mutant p53 and underscore changes in lipid storage as a potential key molecular mechanism in PDAC pathogenesis.
    Keywords:  Cancer; Lipid; Metabolism; p53 mutant
    DOI:  https://doi.org/10.1186/s13062-025-00635-w
  8. EMBO J. 2025 Apr 09.
    Ductal or Ngn3+ cells do not contribute to adult pancreatic islet beta-cell neogenesis in homeostasis.
    Xiuzhen Huang, Huan Zhao, Hui Chen, Zixin Liu, Kuo Liu, Zan Lv, Xiuxiu Liu, Ximeng Han, Maoying Han, Jie Lu, Qiao Zhou, Bin Zhou.
      The adult pancreatic ducts have long been proposed to contain rare progenitors, some of which expressing Ngn3, that generate new beta cells in endocrine-islet homeostasis. Due to their postulated rarity and the lack of definitive markers, the existence or absence of ductal endocrine progenitors remains unsettled despite many studies. Genetic lineage tracing of ductal cells or Ngn3+ cells with currently available CreER drivers has been complicated by off-target labeling of pre-existing beta cells. Here, using dual-recombinase-mediated intersectional genetic strategy and newly-derived Ngn3-2A-CreER and Hnf1b-2A-CreER knock-in drivers, we succeeded in specifically labeling Ngn3-positive cells and Hnf1b-positive ductal cells without marking pre-existing beta cells. These data revealed no evidence of de novo generation of insulin-producing beta cells from ductal cells or endogenous Ngn3-positive cells in the adult pancreas during homeostasis.
    Keywords:  Beta Cell Neogenesis; Ngn3; Pancreatic Ductal Cell; Progenitor
    DOI:  https://doi.org/10.1038/s44318-025-00434-z
  9. J Pept Sci. 2025 May;31(5): e70014
    No Evidence for Plasma Membrane Potential-Independent Cell Penetrating Peptide Direct Translocation.
    Ali Hallaj, Francisco Tomas Ribeiro, Christian Widmann.
      Cell-penetrating peptides (CPPs) are small peptides that can carry bioactive cargoes into cells. CPPs access the cell's cytosol via direct translocation across the plasma membrane. We and others have shown that direct translocation of CPPs occurs through water pores that are formed upon hyperpolarization of the cell's membrane. Direct translocation through water pores can therefore be blocked by depolarizing the plasma membrane. Other direct translocation mechanisms have been proposed that would not rely on membrane hyperpolarization. It has been reported, for example, that in HEK cells, CPP translocation occurs in a plasma membrane potential-independent manner, in contrast to HeLa cells, where CPP access to the cytosol required plasma membrane hyperpolarization. To address these apparent discrepant data, we have tested the requirement of plasma membrane hyperpolarization in a series of cell lines, including HEK and HeLa cells, for CPP direct translocation. Our data, obtained from a wide range of CPP concentrations, show that efficient direct translocation always requires plasma membrane hyperpolarization. We discuss the possible reasons why earlier studies have not evidenced the importance of the plasma membrane potential in the cytosolic uptake of CPPs in some cell lines.
    Keywords:  Plasma membrane potential; cell‐penetrating peptides; direct translocation
    DOI:  https://doi.org/10.1002/psc.70014
  10. Nat Rev Mol Cell Biol. 2025 Apr 09.
    Recommendations for robust and reproducible research on ferroptosis.
    Eikan Mishima, Toshitaka Nakamura, Sebastian Doll, Bettina Proneth, Maria Fedorova, Derek A Pratt, José Pedro Friedmann Angeli, Scott J Dixon, Adam Wahida, Marcus Conrad.
      Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.
    DOI:  https://doi.org/10.1038/s41580-025-00843-2
  11. PLoS Biol. 2025 Apr 10. 23(4): e3003111
    Phase separation of the PRPP amidotransferase into dynamic condensates promotes de novo purine synthesis in yeast.
    Masak Takaine, Rikuri Morita, Yuto Yoshinari, Takashi Nishimura.
      De novo purine synthesis (DPS) is up-regulated under conditions of high purine demand to ensure the production of genetic materials and chemical energy, thereby supporting cell proliferation. However, the regulatory mechanisms governing DPS remain unclear. We herein show that PRPP amidotransferase (PPAT), the rate-limiting enzyme in DPS, forms dynamic and motile condensates in Saccharomyces cerevisiae cells under a purine-depleted environment. The formation and maintenance of condensates requires phase separation, which is driven by target of rapamycin complex 1 (TORC1)-induced ribosome biosynthesis. The self-assembly of PPAT molecules facilitates condensate formation, with intracellular PRPP and purine nucleotides both regulating this self-assembly. Moreover, molecular dynamics simulations suggest that clustering-mediated PPAT activation occurs through intermolecular substrate channeling. Cells unable to form PPAT condensates exhibit growth defects, highlighting the physiological importance of condensation. These results indicate that PPAT condensation is an adaptive mechanism that regulates DPS in response to both TORC1 activity and cellular purine demands.
    DOI:  https://doi.org/10.1371/journal.pbio.3003111
  12. Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00312-2. [Epub ahead of print]44(4): 115541
    PLK1 blockade enhances the anti-tumor effect of MAPK inhibition in pancreatic ductal adenocarcinoma.
    Ben Zhao, Rui Fang, Hendrik Schürmann, Erik Jan Hemmer, Gina Lauren Mayer, Marija Trajkovic-Arsic, Kristina Althoff, Jiajin Yang, Laura Godfrey, Sven T Liffers, Konstantinos Savvatakis, Madeleine Dorsch, Barbara M Grüner, Stephan Hahn, Marc Remke, Smiths S Lueong, Jens T Siveke.
      Despite constitutive Ras/Raf/MAPK pathway activation in most pancreatic ductal adenocarcinomas (PDACs), treatment approaches targeting this pathway have primarily been unsuccessful. We conduct a drug library screen on an MEK inhibitor (MEKi)-resistant PDAC model and perform complementary pathway analysis to identify cellular resistance phenotypes. We use syngeneic models to investigate the molecular determinants of identified drug synergism. Our study reveals an enrichment for the hallmarks of G2/M checkpoints in MEKi-resistant phenotypes from all investigated models. We find overexpression of Polo-like kinase 1 (PLK1) and other G2/M checkpoint-related proteins in MEKi-resistant cells. We identify synergistic activity between MEK and PLK1 inhibition both in vitro and in vivo and mechanistically show that dual inhibition of the PLK1 and MEK pathways activates the JNK/c-JUN pathway. This causes the accumulation of DNA damage, ultimately leading to apoptotic cell death. Dual PLK1/MEK inhibition emerges as a promising targeted approach in PDAC.
    Keywords:  CP: Cancer; G1 arrest; G2/M checkpoint; JNK; KRAS; MAPK; MEK; PDAC; PDO; PLK1; cJUN; cell cycle; organoids; synergism; therapy resistance; trametinib; volasertib
    DOI:  https://doi.org/10.1016/j.celrep.2025.115541
  13. Biophys J. 2025 Apr 03. pii: S0006-3495(25)00211-5. [Epub ahead of print]
    Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
    Mangyu Choe, Tal Einav, Rob Phillips, Denis V Titov.
      Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.
    Keywords:  allosteric feedback; glycolysis; metabolism; modeling
    DOI:  https://doi.org/10.1016/j.bpj.2025.03.037
  14. Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00066-8. [Epub ahead of print]60(7): 982-993
    Mechanisms of ferroptosis sensitization and resistance.
    Weaverly Colleen Lee, Scott J Dixon.
      Ferroptosis is an iron-dependent and oxidative form of non-apoptotic cell death with roles in development, homeostasis, and disease. Ferroptosis sensitivity can vary between cells, often for reasons that are not well understood. In this perspective, we describe the core ferroptosis mechanism and outline how changes in iron, redox, and lipid metabolism can alter ferroptosis sensitivity. We propose the concept of a ferroptosis sensitivity-resistance continuum to describe how different intrinsic and extrinsic factors interact to push cells toward a more ferroptosis-sensitive or ferroptosis-resistant state, with effects on development and diseases such as cancer.
    Keywords:  GPX4; cancer; development; ferroptosis; glutathione; iron; lipid peroxidation; necrosis; neurodegeneration; system xc(−)
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.004
  15. Cancer Cell. 2025 Apr 07. pii: S1535-6108(25)00132-1. [Epub ahead of print]
    Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.
    Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Jack A Roth, Nicholas Navin, Albert C Koong, Mingjian James You, Steven H Lin, Boyi Gan.
      Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.
    Keywords:  copper; cuproptosis; metallothionein; radioresistance; radiotherapy
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.031
  16. Cancer Res. 2025 Apr 11.
    Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties.
    Joshua Cumming, Parniyan Maneshi, Mitesh Dongre, Tala Alsaed, Mohammad Javad Dehghan-Nayeri, Agnes Ling, Kristian Pietras, Cedric Patthey, Daniel Öhlund.
      Within the stroma of pancreatic ductal adenocarcinoma (PDAC), mesenchymal cells differentiate into cancer-associated fibroblast (CAF) subtypes that differentially mediate disease progression. Defining the regulatory mechanism and diversity of CAF subtypes could identify potential therapeutic strategies to harness the tumor suppressive activities of CAFs. To address this, we utilized single-cell RNA sequencing to profile fibroblast activation protein-alpha (FAP) expressing mesenchymal cells in human PDAC. The mesenchymal subpopulations in PDAC reflected mesenchymal cell heterogeneity found in the normal developing pancreas. In addition to characterizing inflammatory CAF (iCAF) and myofibroblastic CAF (myCAF) subpopulations in detail, the analysis uncovered a previously undescribed interferon-response CAF (ifCAF) subtype. Tumor-derived signals induced specific CAF subtypes from pancreatic stellate cells (PSCs) in an organoid-based co-culture model, and time-course experiments revealed regulatory mechanisms that govern subtype formation. STING agonists promoted an ifCAF phenotype in vivo and in vitro. Importantly, induction of an ifCAF phenotype suppressed tumor cell invasiveness and induced an anti-tumor phenotype in tumor-associated neutrophils. Together, this study resolves FAP+ stromal cell heterogeneity in PDAC and identifies an ifCAF subtype that can be induced to suppress pro-tumorigenic features of PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3252
  17. Gastroenterology. 2025 Apr 07. pii: S0016-5085(25)00603-1. [Epub ahead of print]
    KRASG12D cells override homeostatic cell elimination mechanisms in adult pancreas via Wnt5a and cell dormancy.
    Beatriz Salvador-Barbero, Markella Alatsatianos, Jennifer P Morton, Owen J Sansom, Catherine Hogan.
       BACKGROUND AND AIMS: PaperClip The adult pancreas protects against cancer by actively expelling genetically mutated cells. Pancreatic cancer starts with cells carrying KRAS mutations; however, it is not clear how some KRAS mutant cells override cell elimination mechanisms to survive in tissues. Methods We used an in vivo mouse model of sporadic tumorigenesis to induce Kras and/or Tp53 mutations in low numbers of cells in the adult pancreas. We monitored mutant cell fate over time using quantitative fluorescence imaging. Gene signatures of non-eliminated mutant cell populations were identified using bulk RNA sequencing. Differential gene expression was overlapped with publicly available datasets. Key molecular pathways were validated in murine pancreas using immunofluorescence and functionally tested using inhibitor studies in vivo and epithelial co-culture systems in vitro. Results While most genetically mutant cells are eliminated from the adult pancreas, a population of KRASG12D- or p53R172H-expressing cells are stably retained. We identify Wnt5a signalling, cell dormancy and stemness as key features of surviving KrasG12D cells in vivo. Wnt5a specifically inhibits apical extrusion of RasV12 cells by promoting stable E-cadherin-based cell-cell adhesions at RasV12: normal cell-cell boundaries in vitro. In the pancreas, Wnt signalling, E-cadherin and β-catenin are increased at cell-cell contacts between non-eliminated KrasG12D cells and normal neighbours. Active Wnt signalling is a general mechanism required to promote KrasG12D and p53R172H cell retention and cell survival in vivo. Conclusions RAS mutant cells activate Wnt5a and cell dormancy to avoid cell expulsion and to survive in the adult pancreas.
    Keywords:  Cell competition; Cell dormancy; Cell extrusion; Early tumorigenesis; Epithelial homeostasis; Oncogenic RAS; Pancreatic cancer; Wnt5a
    DOI:  https://doi.org/10.1053/j.gastro.2025.02.042
  18. Science. 2025 Apr 11. 388(6743): eadm8857
    A neuroimmune circuit mediates cancer cachexia-associated apathy.
    Xiaoyue Aelita Zhu, Sarah Starosta, Miriam Ferrer, Junxiao Hou, Quentin Chevy, Federica Lucantonio, Rodrigo Muñoz-Castañeda, Fengrui Zhang, Kaikai Zang, Xiang Zhao, Francesca R Fiocchi, Mason Bergstrom, Aubrey A Siebels, Thomas Upin, Michael Wulf, Sarah Evans, Alexxai V Kravitz, Pavel Osten, Tobias Janowitz, Marco Pignatelli, Adam Kepecs.
      Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti-IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.
    DOI:  https://doi.org/10.1126/science.adm8857
  19. EMBO J. 2025 Apr 07.
    Interferon-induced PARP14-mediated ADP-ribosylation in p62 bodies requires the ubiquitin-proteasome system.
    Rameez Raja, Banhi Biswas, Rachy Abraham, Yiran Wang, Che-Yuan Chang, Ivo A Hendriks, Sara C Buch-Larsen, Hongrui Liu, Xingyi Yang, Chenyao Wang, Hien Vu, Anne Hamacher-Brady, Danfeng Cai, Anthony K L Leung.
      Biomolecular condensates are cellular compartments without enveloping membranes, enabling them to dynamically adjust their composition in response to environmental changes through post-translational modifications. Recent work has revealed that interferon-induced ADP-ribosylation (ADPr), which can be reversed by a SARS-CoV-2-encoded hydrolase, is enriched within a condensate. However, the identity of the condensate and the responsible host ADP-ribosyltransferase remain elusive. Here, we demonstrate that interferon induces ADPr through transcriptional activation of PARP14, requiring both the physical presence and catalytic activity of PARP14 for condensate formation. Interferon-induced ADPr colocalizes with PARP14 and its associated E3 ligase, DTX3L. These PARP14/ADPr condensates contain key components of p62 bodies-including the selective autophagy receptor p62, its binding partner NBR1 and the associated protein TAX1BP1, along with K48-linked and K63-linked polyubiquitin chains-but lack the autophagosome marker LC3B. Knockdown of p62 disrupts the formation of these ADPr condensates. Importantly, these structures are unaffected by autophagy inhibition, but depend on ubiquitination and proteasome activity. Taken together, these findings demonstrate that interferon triggers PARP14-mediated ADP-ribosylation in p62 bodies, which requires an active ubiquitin-proteasome system.
    Keywords:  ADP-Ribosylation; Condensates; Interferon; Ubiquitin-Proteasome System; p62
    DOI:  https://doi.org/10.1038/s44318-025-00421-4
  20. Cell Death Dis. 2025 Apr 05. 16(1): 254
    Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
    Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.
      Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-025-07510-6
  21. Mol Metab. 2025 Apr 07. pii: S2212-8778(25)00043-2. [Epub ahead of print] 102136
    Estrogenic activity of E2-conjugated GLP-1 is mediated by intracellular endolysosomal acidification and estrone metabolism.
    Callum Coupland, Na Sun, Ahmed Khalil, Özüm Ezgi Karaoglu, Arkadiusz Liskiewicz, Daniela Liskiewicz, Gerald Grandl, Seun Akindehin, Gandhari Maity, Bin Yang, Brian Finan, Patrick Knerr, Jonathan D Douros, Axel Walch, Richard DiMarchi, Matthias H Tschöp, Timo D Müller, Aaron Novikoff.
      Recent modifications to glucagon-like peptide 1 (GLP-1), known for its insulinotropic and satiety-inducing effects, have focused on conjugating small molecules to enable selective delivery into GLP-1R+ tissues to achieve targeted synergy and improved metabolic outcomes. Despite continued advancements in GLP-1/small molecule conjugate strategies, the intracellular mechanisms facilitating concurrent GLP-1R signaling and small molecule cargo release remain poorly understood. We evaluate an estradiol (E2)-conjugated GLP-1 (GLP-1-CEX/E2) for relative differences in GLP-1R signaling and trafficking, and elucidate endolysosomal dynamics that lead to estrogenic activity using various live-cell, reporter, imaging, and mass-spectrometry techniques. We find GLP-1-CEX/E2 does not differentially activate or traffic the GLP-1R relative to its unconjugated GLP-1 backbone (GLP-1-CEX), but uniquely internalizes the E2 moiety and stimulates estrogenic signaling. Endolysosomal pH-dependent proteolytic activity likely mediates E2 moiety liberation, as evidenced by clear amplification in estrogenic activity following co-administration with lysosomal VATPase activator EN6. The hypothesized liberated metabolite from GLP-1-CEX/E2, E2-3-ether, exhibits partial estrogenic efficacy through ERα, and is predisposed toward estrone-3-sulfate conversion. Finally, we identify relative increases in intracellular E2, estrone, and estrone-3-sulfate following GLP-1-CEX/E2 incubation in GLP-1R+ cells, demonstrating proof-of-principle for desired cargo release. Together, our data suggest that GLP-1-CEX/E2 depends on GLP-1R trafficking and lysosome acidification for estrogenic efficacy, with a likely conversion of the liberated E2-3-ether metabolite into estrone-3-sulfate, resulting in residual downstream flux into active estradiol. Our current findings aim to improve the understanding of small molecule targeting and the efficacy behind GLP-1/small molecule conjugates.
    Keywords:  Bioluminescent resonance energy transfer (BRET); Estradiol; Glucagon-like peptide 1; Metabolomics; Peptide conjugation; Pharmacology
    DOI:  https://doi.org/10.1016/j.molmet.2025.102136
  22. RSC Adv. 2025 Apr 09. 15(15): 11343-11353
    Mechanistic insights from simulations of drug-drug conjugate nanoclusters for co-delivery across cancer cell membranes.
    Cherdpong Choodet, Unnop Srikulwong, Pakawat Toomjeen, Adulvit Chuaephon, Witthawat Phanchai, Theerapong Puangmali.
      Amphiphilic drug-drug conjugates (ADDCs) such as gemcitabine-camptothecin (GEM-CPT) and doxorubicin-10-hydroxycamptothecin (DOX-HCPT) nanoclusters offer innovative solutions to overcome the limitations of conventional cancer therapies, including poor solubility and nonspecific targeting. Using molecular dynamics (MD) simulations, we explored the mechanisms by which these nanoclusters interact with and penetrate cancer and normal cell membranes. GEM-CPT exhibited enhanced membrane penetration in cancer cells through combined hydrophilic and hydrophobic interactions, along with its ability to extract cholesterol and induce membrane remodelling. In contrast, DOX-HCPT maintained structural integrity through stable π-π stacking interactions, showing selective binding to membrane head groups (HG) with minimal cholesterol interaction, particularly in normal membranes. The GEM-CPT nanocluster disrupted the cancer membrane by inducing asymmetric lipid distribution and facilitating water infiltration, whereas the hydrophobic DOX-HCPT repelled water, maintaining membrane stability. The size of the nanocluster further influenced the behaviour; larger clusters drove steric assembly and lipid reorganisation, while smaller clusters achieved deeper penetration at the cost of structural integrity. The contrasting behaviours of GEM-CPT and DOX-HCPT highlight the critical roles of size, charge, and amphiphilicity in membrane transport mechanisms. These findings provide valuable insights into the design of efficient and selective nanomedicines, paving the way for optimised drug delivery systems with reduced off-target effects.
    DOI:  https://doi.org/10.1039/d5ra00480b
  23. EMBO J. 2025 Apr 07.
    Nuclear envelope-associated lipid droplets are enriched in cholesteryl esters and increase during inflammatory signaling.
    Ábel Szkalisity, Lauri Vanharanta, Hodaka Saito, Csaba Vörös, Shiqian Li, Antti Isomäki, Teemu Tomberg, Clare Strachan, Ilya Belevich, Eija Jokitalo, Elina Ikonen.
      Cholesteryl esters (CEs) and triacylglycerols (TAGs) are stored in lipid droplets (LDs), but their compartmentalisation is not well understood. Here, we established a hyperspectral stimulated Raman scattering microscopy system to identify and quantitatively assess CEs and TAGs in individual LDs of human cells. We found that nuclear envelope-associated lipid droplets (NE-LDs) were enriched in cholesteryl esters compared to lipid droplets in the cytoplasm. Correlative light-volume-electron microscopy revealed that NE-LDs projected towards the cytoplasm and associated with type II nuclear envelope (NE) invaginations. The nuclear envelope localization of sterol O-acyltransferase 1 (SOAT1) contributed to NE-LD generation, as trapping of SOAT1 to the NE further increased their number. Upon stimulation by the pro-inflammatory cytokine TNFα, the number of NE-LDs moderately increased. Moreover, TNFα-induced NF-κB nuclear translocation was fine-tuned by SOAT1: increased SOAT1 activity and NE-LDs associated with faster NF-κB translocation, whereas reduced SOAT1 activity and NE-LDs associated with slower NF-κB translocation. Our findings suggest that the NE is enriched in CEs and that cholesterol esterification can modulate nuclear translocation.
    Keywords:  Label-Free Imaging; Lipid Droplet; Neutral Lipid; Nuclear Envelope
    DOI:  https://doi.org/10.1038/s44318-025-00423-2
  24. J Cell Biol. 2025 Jun 02. pii: e202411092. [Epub ahead of print]224(6):
    The autophagy protein ATG-9 regulates lysosome function and integrity.
    Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N Noda, Hong Zhang.
      The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.
    DOI:  https://doi.org/10.1083/jcb.202411092
  25. Acta Biomater. 2025 Apr 04. pii: S1742-7061(25)00254-5. [Epub ahead of print]
    Contact-free characterization of nuclear mechanics using correlative Brillouin-Raman Micro-Spectroscopy in living cells.
    S Kerdegari, A A Passeri, F Morena, G Ciccone, V Bazzurro, P Canepa, A Lagomarsino, S Martino, M Mattarelli, M Vassalli, A Diaspro, S Caponi, C Canale.
      Nuclear mechanics is a key parameter in regulating cell physiology, affecting chromatin accessibility and transcriptional regulation. The most established method to characterize the mechanics of biological materials at the sub-micrometer scale is based on atomic force microscopy (AFM). However, its contact-based nature limits the direct access to the nucleus. While some indirect methods have been proposed to measure nuclear mechanics in living cells, the readout is influenced by the overlaying cytoskeleton. For this reason, mechanical measurements on isolated nuclei are a common strategy to overcome this issue. However, the impact of the invasive preparation procedure on the measured properties is still unclear. To address this issue, we studied the mechanical properties of skin fibroblasts probing the nuclear region and of extracted nuclei using AFM and correlative Brillouin-Raman Micro-Spectroscopy (BRMS). The latter technique is a non-invasive method to image living systems in 3D, obtaining correlative information on the mechanical and chemical properties of the sample at specific points of interest. Using this approach, we demonstrated that extracted nuclei are significantly softer than intact ones. Moreover, we demonstrated the ability of BRMS to highlight mechanical features within living cells that were masked by the convolution with the cytosol in conventional AFM measurements. Overall, this study shows the importance of evaluating nuclear mechanics within the native environment where cellular homeostasis is preserved. We, therefore, suggest that BRMS offers a much deeper insight into nuclear mechanics compared to AFM, and it should be adopted as a reference tool to study nuclear mechanobiology. STATEMENT OF SIGNIFICANCE: The cell nucleus, the largest eukaryotic organelle, is crucial for cellular function and genetic material storage. Its mechanical properties, often altered in disease, influence key processes like chromatin accessibility. Although atomic force microscopy (AFM) is a standard method for studying nuclear mechanics, isolating nuclear stiffness in living cells is challenging due to interference from the cytoskeleton and plasma membrane. We demonstrate that correlative Brillouin-Raman Micro-Spectroscopy (BRMS) enables non-contact, high-resolution measurement of nuclear mechanics, capturing sub-micron details. We compare the results from BRMS with that obtained on the same samples with AFM. BRMS enhances our understanding of nuclear stiffness in physiological conditions, offering valuable insights for researchers in the field of mechanobiology, biotechnology, medicine, and bioengineering.
    Keywords:  AFM; Brillouin microscopy; Mechanobiology; Nuclear mechanics; Raman spectroscopy
    DOI:  https://doi.org/10.1016/j.actbio.2025.04.009
  26. Nature. 2025 Apr 09.
    Stress dynamically modulates neuronal autophagy to gate depression onset.
    Liang Yang, Chen Guo, Zhiwei Zheng, Yiyan Dong, Qifeng Xie, Zijian Lv, Min Li, Yangyang Lu, Xiaonan Guo, Rongshan Deng, Yiqin Liu, Yirong Feng, Ruiqi Mu, Xuliang Zhang, Huan Ma, Zhong Chen, Zhijun Zhang, Zhaoqi Dong, Wei Yang, Xiangnan Zhang, Yihui Cui.
      Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of brain homeostasis2, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.
    DOI:  https://doi.org/10.1038/s41586-025-08807-4
  27. Mech Ageing Dev. 2025 Apr 06. pii: S0047-6374(25)00032-6. [Epub ahead of print] 112056
    A Novel Platform for Precise Senolysis.
    Conti Anastasia, Di Micco Raffaella.
      The selective eradication of senescent cells using senolytic compounds represents a promising strategy to treat senescence-associated diseases like aging and cancer. However, many senolytics may cause systemic toxicity. Magkouta et al., writing in Nature Aging, introduced mGL392, an advanced senolytic platform utilizing a lipofuscin-binding domain scaffold conjugated with a senolytic drug (e.g., dasatinib). mGL392 effectively eliminates senescent cells in vitro and in vivo, reducing tumor size in melanoma models while minimizing systemic toxicity. Compared to existing senolytics, it offers improved specificity, reducing off-target effects. This innovation presents a safer and more effective approach for treating senescence-related diseases.
    Keywords:  aging and cancer; cellular senescence; senescent cells eradication; senolytic platform
    DOI:  https://doi.org/10.1016/j.mad.2025.112056
  28. Trends Endocrinol Metab. 2025 Apr 07. pii: S1043-2760(25)00053-0. [Epub ahead of print]
    Integrating cancer medicine into metabolic rhythms.
    Keyu Su, Deshun Zeng, Weiru Zhang, Fei Peng, Bai Cui, Quentin Liu.
      Circadian rhythms are cell-intrinsic time-keeping mechanisms that allow organisms to adapt to 24-h environmental changes, ensuring coordinated physiological functions by aligning internal metabolic oscillations with external timing cues. Disruption of daily metabolic rhythms is associated with pathological events such as cancer development, yet the mechanisms by which perturbed metabolic rhythms contribute to tumorigenesis remain unclear. Herein we review how circadian clocks drive balanced rhythmic metabolism which in turn governs physiological functions of locomotor, immune, and neuroendocrine systems. Misaligned metabolic rhythms cause pathological states which further drive cancer initiation, progression, and metastasis. Restoring the balance of metabolic rhythms with chemical, hormonal, and behavioral interventions serves as a promising strategy for cancer therapy.
    Keywords:  biological rhythms; cancer chronotherapy; circadian clocks; metabolic disorder
    DOI:  https://doi.org/10.1016/j.tem.2025.03.007
  29. EMBO Rep. 2025 Apr 04.
    Espin enhances confined cell migration by promoting filopodia formation and contributes to cancer metastasis.
    Yan Wang, Peng Shi, Geyao Liu, Wei Chen, Ya-Jun Wang, Yiping Hu, Ao Yang, Tonghua Wei, Yu-Chen Chen, Ling Liang, Zheng Liu, Yan-Jun Liu, Congying Wu.
      Genes regulating the finger-like cellular protrusions-filopodia have long been implicated in cancer metastasis. However, depleting the flat lamellipodia but retaining filopodia drastically hampers cell migration on spread surface, obscuring the role of filopodia in cell motility. It has been noticed recently that cells under confinement may employ distinct migratory machineries. However, the regulating factors have mainly been focused on cell blebbing, nuclear deformation and cell rear contractility, without much emphasis on cell protrusions and even less on filopodia. Here, by micropore-based screening, we identified espin as an active regulator for confined migration and that its overexpression was associated with metastasis. In comparison to fascin, espin showed stronger actin bundling in vitro and induced shorter and thicker filopodia in cells. Combining the imaging-compatible microchannels and DNA-based tension probes, we uncovered that espin overexpression induced excessive filopodia at the leading edge and along the sides, exerting force for confined migration. Our results demonstrate an important role for filopodia and the regulating protein-espin in confined cell migration and shed new light on cytoskeletal mechanisms underlying metastasis.
    Keywords:  Cancer Metastasis; Confined Migration; Espin; Filopodia
    DOI:  https://doi.org/10.1038/s44319-025-00437-1
  30. Mol Biol Cell. 2025 Apr 09. mbcE24090394
    Cell Confluency Affects p53 Dynamics in Response to DNA Damage.
    Alina Simerzin, Emily E Ackerman, Kotaro Fujimaki, Rainer H Kohler, Yoshiko Iwamoto, Mathias S Heltberg, Ashwini Jambhekar, Ralph Weissleder, Galit Lahav.
      The tumor suppressor protein p53 plays a key role in the cellular response to DNA damage. In response to DNA double strand breaks (DSB), cultured cells exhibit oscillations of p53 levels, which impact gene expression and cell fate. The dynamics of p53 in-vivo have only been studied in fixed tissues or using reporters for p53's transcriptional activity. Here we established breast tumors expressing a fluorescent reporter for p53 levels and employed intravital imaging to quantify its dynamics in response to DSB in-vivo. Our findings revealed large heterogeneity among individual cells, with most cells exhibiting a single prolonged pulse. We then tested how p53 dynamics might change under high cell confluency, one factor that differs between cell culture and tissues. We revealed that highly confluent cultured breast cancer cells also show one broad p53 pulse instead of oscillations. Through mathematical modeling, sensitivity analysis and live cell imaging we identified low levels of the phosphatase Wip1, a transcriptional target and negative regulator of p53, as a key contributor to these dynamics. Since high cell confluency better reflects the microenvironment of tissues, the impact of cell confluency on p53 dynamics may have important consequences for cancerous tissues responding to DNA damage inducing therapies.
    DOI:  https://doi.org/10.1091/mbc.E24-09-0394
  31. Nat Commun. 2025 Apr 09. 16(1): 3375
    Peripheral positioning of lysosomes supports melanoma aggressiveness.
    Katerina Jerabkova-Roda, Marina Peralta, Kuang-Jing Huang, Antoine Mousson, Clara Bourgeat Maudru, Louis Bochler, Ignacio Busnelli, Rabia Karali, Hélène Justiniano, Lucian-Mihai Lisii, Philippe Carl, Vincent Mittelheisser, Nandini Asokan, Annabel Larnicol, Olivier Lefebvre, Hugo Lachuer, Angélique Pichot, Tristan Stemmelen, Anne Molitor, Léa Scheid, Quentin Frenger, Frédéric Gros, Aurélie Hirschler, François Delalande, Emilie Sick, Raphaël Carapito, Christine Carapito, Dan Lipsker, Kristine Schauer, Philippe Rondé, Vincent Hyenne, Jacky G Goetz.
      Emerging evidence suggests that the function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how their function is linked to their position and how this controls metastasis remains elusive. Here, we analyze lysosome subcellular distribution in patient-derived melanoma cells and patient biopsies and show that lysosome spreading scales with melanoma aggressiveness. Peripheral lysosomes promote matrix degradation and cell invasion which is directly linked to the lysosomal and cell transcriptional programs. Using chemo-genetical control of lysosome positioning, we demonstrate that perinuclear clustering impairs lysosome secretion, matrix degradation and invasion. Impairing lysosome spreading significantly reduces invasive outgrowth in two in vivo models, mouse and zebrafish. Our study provides a direct demonstration that lysosome positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis and suggesting its potential utility for diagnosis of metastatic melanoma.
    DOI:  https://doi.org/10.1038/s41467-025-58528-5
  32. Mol Cell. 2025 Mar 28. pii: S1097-2765(25)00202-3. [Epub ahead of print]
    Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis.
    Chuan Gao, Ang Gao, Yulong Jiang, Ronghui Gao, Yan Guo, Zirou Peng, Weiwei Jiang, Mengyao Zhang, Zirui Zhou, Chaojun Yan, Wentong Fang, Hankun Hu, Guangya Zhu, Jing Zhang.
      Hypoxia and dysregulated phase separation can both activate oncogenic transcriptomic profiles. However, whether hypoxia regulates transcription-associated phase separation remains unknown. Here, we find that zinc fingers and homeoboxes 2 (ZHX2) undergoes phase separation in response to hypoxia, promoting their occupancy on chromatin and activating a cluster of oncogene transcription that is enriched by metastatic genes distinct from the targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Hypoxia induces ZHX2 phase separation via a proline-rich intrinsically disordered region (IDR), enhancing phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTC-binding factor (CTCF) in condensates to alter chromatin looping, consequently driving metastatic gene transcription and cancer metastasis. Our findings provide significant insight into oncogene activation and suggest a phase-separation-based therapeutic strategy for cancer.
    Keywords:  CTCF; ZHX2; chromatin looping; hypoxia; metastasis; phase separation
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.009
  33. Physiol Behav. 2025 Apr 05. pii: S0031-9384(25)00110-6. [Epub ahead of print] 114909
    The role of the hypothalamus in the development of cancer cachexia.
    Dimitrios Stagikas, Yannis Vasileios Simos, Lampros Lakkas, Panagiotis Filis, Dimitrios Peschos, Konstantinos Ioannis Tsamis.
      Cachexia is a complex multiorgan syndrome associated with various chronic diseases, characterized by anorexia and increased tissue wasting in the context of chronic inflammation. A specific form of this syndrome, known as cancer cachexia (CC), occurs alongside different types of tumors. The pathogenesis of CC is multifactorial. Inflammatory mediators and hormones released by both tumor and host cells have a relevant role in driving the peripheral catabolic process through several direct mechanisms. Accumulating evidence indicates that the central nervous system (CNS) plays an integral role in the pathogenesis of CC. The hypothalamus has emerged as a critical brain region that senses and amplifies peripheral stimuli, generating inappropriate neuronal signaling and leading to the dysregulation of energy homeostasis under cachexia conditions. Circulating cytokines may act in concert with hormones and neurotransmitters and perturb critical hypothalamic neurocircuits shifting their activity towards the anorexigenic pathway and increase of energy expenditure. This review discusses the mechanisms mediating the hypothalamic homeostatic imbalance in the context of anorexia and cachexia associated with cancer.
    Keywords:  Cancer cachexia; anorexia; cytokines; hypothalamus; neuroinflammation; neurotransmitters
    DOI:  https://doi.org/10.1016/j.physbeh.2025.114909
  34. Cancer Res. 2025 Apr 09.
    From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.
    Camille Attané, Catherine Muller.
      Adipocytes from white adipose tissue support cancer progression by supplying fatty acids to tumor cells while cold-activated brown adipose tissue has been shown to inhibit tumor growth by disrupting cancer cell metabolism. In a groundbreaking study published in Nature Biotechnology, Nguyen and colleagues developed Adipose-Modified Therapy (AMT), a strategy that genetically reprograms white adipocytes to outcompete tumors for key nutrients. Using CRISPR activation technology, researchers enhanced adipocyte glucose and fatty acid consumption, by inducing a stable browning phenotype. In vitro, browned adipocytes reduced glycolysis and fatty acid oxidation in cancer cells, inhibiting their proliferation. Implantation of engineered adipose organoids adjacent to tumors suppressed tumor growth, reduced angiogenesis, and altered metabolic gene expression in xenograft models. AMT also prevented tumor development in genetic mouse models of cancer, suggesting a role in cancer prevention. Finally, modified human mammary adipocytes inhibited the growth of patient-derived breast cancer organoids. This therapy, based on autologous fat transplantation, could offer a reversible and patient-specific approach. Challenges remain, including metabolic plasticity in cancer cells and the fragility of mature adipocytes in cell culture. AMT represents a paradigm shift in cancer therapy, leveraging adipocytes as metabolic competitors rather than tumor facilitators, opening new avenues for metabolism-targeted cancer treatments.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1511
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